Polysarcosine as PEG Alternative for Enhanced Camptothecin-Induced Cancer Immunogenic Cell Death.

Nanomedicine-enhanced immunogenic cell death (ICD) has attracted considerable attention for its great potential in cancer treatment. Even though polyethylene glycol (PEG) is widely recognized as the gold standard for surface modification of nanomedicines, some shortcomings associated with this PEGylation, such as hindered cell endocytosis and accelerated blood clearance phenomenon, have been revealed in recent years. Notably, polysarcosine (PSar) as a highly biocompatible polymer can be finely synthesized by mild ring-opening polymerization (ROP) of sarcosine N-carboxyanhydrides (Sar-NCAs) and exhibit great potential as an alternative to PEG. In this article, PSar-b-polycamptothecin block copolymers are synthesized by sequential ROP of camptothecin-based NCAs (CPT-NCAs) and Sar-NCAs. Then, the detailed and systematic comparison between PEGylation and PSarylation against the 4T1 tumor model indicates that PSar decoration can facilitate the cell endocytosis, greatly enhancing the ICD effects and antitumor efficacy. Therefore, it is believed that this well-developed PSarylation technique will achieve effective and precise cancer treatment in the near future.

Facile Preparation of Polysarcosine-Tethered Inorganic Nanospheres by Using Unimolecular Polypept(o)ides as Template.

Polymer-inorganic nanocomposites that integrate the advantages of both polymers and inorganic nanoparticles (NPs) are broadly exploited for versatile applications. Especially, emerging polymer-templated preparation of inorganic NPs has drawn extensive attention, which is ascribed to simplified synthesis and feasible tunability. However, how to precisely fabricate biocompatible polymer-inorganic NPs remains unsolved. In this article, by mild ring opening polymerization (ROP) of ß-benzyl L-aspartate N-carboxyanhydrides (BLA-NCAs) and sarcosine N-carboxyanhydrides (Sar-NCAs) and subsequent debenzylation, a series of poly(amino acid)-based unimolecular micelles (PAMAM-g-(PLA-b-PSar)) are facilely synthesized. Afterward, by utilization of these star-like polymers as template, the controllable preparation of various PSar-tethered inorganic NPs is investigated and characterized meticulously. This general strategy for the preparation of PSar-tethered inorganic NPs can bring a great chance for future fabrication of biomedical nanoplatforms.

Glucose-responsive enzymatic biomimetic nanodots for H2O2 self-supplied catalytic photothermal/chemodynamic anticancer therapy.

Photothermal therapy (PTT) combined with chemodynamic therapy (CDT) presents an appealing complementary anti-tumor strategy, wherein PTT accelerates the production of reactive oxygen species (ROS) in CDT and CDT eliminates residual tumor tissues that survive from PTT treatment. However, nanomaterials utilized in PTT/CDT are limited by non-specific damage to the entire organism. Herein, a glucose-responsive enzymatic Fe@HRP-ABTS/GOx nanodot is judiciously designed for tumor-specific PTT/CDT via a simple and clean protein-templated biomimetic mineralization synthesis. By oxidizing glucose in tumor cells, glucose oxidase (GOx) activates glucose-responsive tumor therapy and increases the concentration of H2O2 at the tumor site. More importantly, the self-supplied peroxide hydrogen (H2O2) can convert ABTS (2,2'-Hydrazine-bis(3-ethylbenzothiazoline-6-sulfonic acid) diamine salt) into oxidized ABTS (oxABTS) through horseradish peroxidase (HRP) catalysis for PTT and photoacoustic (PA) imaging. Furthermore, the Fe2+ arising from the reduction of Fe3+ by overexpressed GSH reacts with H2O2 to generate intensely reactive •OH through the Fenton reaction, concurrently depleting GSH and inducing efficient tumor CDT. The in vitro and in vivo experiments demonstrate superior cancer cell killing and tumor eradication effect of Fe@HRP-ABTS/GOx nanodot under near-infrared (NIR) laser irradiation. Collectively, the nanodots provide mutually reinforcing catalytic PTT/CDT anti-tumor strategies for treating liver cancer and potentially other malignancies. STATEMENT OF SIGNIFICANCE: Combinatorial antitumor therapy with nanomedicines presents great prospects for development. However, the limitation of non-specific damage to normal tissues hinders its further clinical application. In this work, we fabricated tumor-selective biomimetic Fe@HRP-ABTS/GOx nanodots for H2O2 self-supplied catalytic photothermal/chemodynamic therapy of tumors. The biomimetic synthesis strategy provides the nanodots with enzymatic activity in response to glucose to produce H2O2. The self-supplied H2O2 initiates photothermal therapy with oxidized ABTS and enhances chemodynamic therapy through simultaneous •OH generation and GSH depletion. Our work provides a new paradigm for developing tumor-selective catalytic nanomedicines and will guide further clinical translation of the enzymatic biomimetic synthesis strategy.

Polymerization-Induced Self-Assembly for Efficient Fabrication of Biomedical Nanoplatforms.

Amphiphilic copolymers can self-assemble into nano-objects in aqueous solution. However, the self-assembly process is usually performed in a diluted solution (<1 wt%), which greatly limits scale-up production and further biomedical applications. With recent development of controlled polymerization techniques, polymerization-induced self-assembly (PISA) has emerged as an efficient approach for facile fabrication of nano-sized structures with a high concentration as high as 50 wt%. In this review, after the introduction, various polymerization method-mediated PISAs that include nitroxide-mediated polymerization-mediated PISA (NMP-PISA), reversible addition-fragmentation chain transfer polymerization-mediated PISA (RAFT-PISA), atom transfer radical polymerization-mediated PISA (ATRP-PISA), and ring-opening polymerization-mediated PISA (ROP-PISA) are discussed carefully. Afterward, recent biomedical applications of PISA are illustrated from the following aspects, i.e., bioimaging, disease treatment, biocatalysis, and antimicrobial. In the end, current achievements and future perspectives of PISA are given. It is envisioned that PISA strategy can bring great chance for future design and construction of functional nano-vehicles.

Platinum Drug-Incorporating Polymeric Nanosystems for Precise Cancer Therapy.

Platinum (Pt) drugs are widely used in clinic for cancer therapy, but their therapeutic outcomes are significantly compromised by severe side effects and acquired drug resistance. With the emerging immunotherapy and imaging-guided cancer therapy, precise delivery and release of Pt drugs have drawn great attention these days. The targeting delivery of Pt drugs can greatly increase the accumulation at tumor sites, which ultimately enhances antitumor efficacy. Further, with the combination of Pt drugs and other theranostic agents into one nanosystem, it not only possesses excellent synergistic efficacy but also achieves real-time monitoring. In this review, after the introduction of Pt drugs and their characteristics, the recent progress of polymeric nanosystems for efficient delivery of Pt drugs is summarized with an emphasis on multi-modal synergistic therapy and imaging-guided Pt-based cancer treatment. In the end, the conclusions and future perspectives of Pt-encapsulated nanosystems are given.

Acidity/carbon dioxide-sensitive triblock polymer-grafted photoactivated vesicles for programmed release of chemotherapeutic drugs against glioblastoma.

Controllable release of chemotherapeutic drugs in tumor sites remains a big challenge for precision therapy. Herein, we developed acidity/carbon dioxide (H+/CO2)-sensitive poly (ethylene glycol)-b-poly (2-(diisopropylamino) ethyl methacrylate)-b-polystyrene triblock polymer (PEG-b-PDPA-b-PS) grafted photoactivated vesicles for programmed release of chemotherapeutic drugs against glioblastoma. In brief, gold nanoparticles (GNPs) were firstly tethered with the H+/CO2-sensitive PEG-b-PDPA-b-PS polymer. Next, the CO2 precursor (ammonium bicarbonate, NH4HCO3) and doxorubicin (DOX) were loaded during self-assembly process of PEG-b-PDPA-b-PS-tethered GNPs, thus obtaining the multifunctional gold vesicles (denoted as GVND). The programmed multi-stimuli responsive drug release by GVND was undergone in multiple steps as follows: 1) the vesicular architecture of GVND was first swelled in tumor acidic microenvironment, 2) the GVND were partially broken under near-infrared (NIR) laser irradiation, 3) the mild hyperthermia generated by GV triggered the thermal decomposition of encapsulated NH4HCO3, leading to the in situ generation of CO2, 4) the generated CO2 reacted with PDPA of PEG-b-PDPA-b-PS, changing the hydrophilicity and hydrophobicity of GVND, thus vastly breaking its vesicular architecture, finally resulting in a "bomb-like" release of DOX in tumor tissues. Such a multi-stimuli responsive programmed drug delivery and mild hyperthermia under NIR laser activation displayed strong antitumor efficacy and completely eradicated U87MG glioblastoma tumor. This work presented a promising strategy to realize precision drug delivery for chemotherapy against glioblastoma. STATEMENT OF SIGNIFICANCE.

Chemo-Biocascade Reactions Enabled by Metal-Organic Framework Micro-Nanoreactor.

The one-pot combination of biocatalytic and chemocatalytic reactions represents an economically and ecologically attractive concept in the emerging cascade processes for manufacturing. The mutual incompatibility of biocatalysis and chemocatalysis, however, usually causes the deactivation of catalysts, the mismatching of reaction dynamic, and further challenges their integration into concurrent chemo-biocascades. Herein, we have developed a convenient strategy to construct versatile functional metal-organic framework micro-nanoreactors (MOF-MNRs), which can realize not only the encapsulation and protection of biocatalysts but also the controllable transmission of substances and the mutual communication of the incompatible chemo-biosystems. Importantly, the MOFs serving as the shell of MNRs have the capability of enriching the chemocatalysts on the surface and improving the activity of the chemocatalysts to sufficiently match the optimum aqueous reaction system of biocatalysts, which greatly increase the efficiency in the combined concurrent chemo-biocatalysis. Such strategy of constructing MOF-MNRs provides a unique platform for connecting the "two worlds" of chemocatalysis and biocatalysis.

Polymeric Nanoreactors as Emerging Nanoplatforms for Cancer Precise Nanomedicine.

How to precisely detect and effectively cure cancer which is defined as precise nanomedicine has drawn great attention worldwide. Polymeric nanoreactors which can in situ catalyze inert species into activated ones, can greatly increase imaging quality and enhance therapeutic effects along with decreased background interference and reduced serious side effects. After a brief introduction, the design and preparation of polymeric nanoreactors are discussed from the following aspects, that is, solvent-switch, pH-tuning, film rehydration, hard template, electrostatic interaction, and polymerization-induced self-assembly (PISA). Subsequently, the biomedical applications of these nanoreactors in the fields of cancer imaging, cancer therapy, and cancer theranostics are highlighted. The last but not least, conclusions and future perspectives about polymeric nanoreactors are given. It is believed that polymeric nanoreactors can bring a great opportunity for future fabrication and clinical translation of precise nanomedicine.

Wavelength-Selective Light-Controlled Stepwise Photolysis from Single Gold Nanoparticles.

Light-controlled sequential photolysis from a single nanoparticle is a challenge for controlled release. A wavelength-selective sequential photolysis from single gold nanoparticles is reported for the first time. In particular, it is also demonstrated that such nanoparticle can be used to sequentially release two payloads in living cells. In principle, this system can be extended to sequential release of multiple different types of payloads by rational design of diverse photocleavable linkers. It is expected that this work can provide a new tool for better orderly controlling cellular events that request high spatiotemporal manners.

Tumor-Specific Activatable Nanocarriers with Gas-Generation and Signal Amplification Capabilities for Tumor Theranostics.

Multifunctional nanotheranostics are typically designed by integrating multiple functional components. This approach not only complicates the preparation process but also hinders any bioapplication due to the potential toxic effects when each component is metabolized. Here, we report a safe, biodegradable, and tumor-specific nanocarrier that, once activated by the acidic tumor microenvironment (TME), has diagnostic and therapeutic functions suitable for tumor theranostics. Our nanocarrier is composed of biomineralized manganese carbonate (BMC) nanoparticles (NPs) that readily decompose to release Mn2+ ions and CO2 gas in the acidic TME due to its intrinsic pH-dependent solubility. Mn2+ and CO2 release permits magnetic resonance and ultrasound imaging of tumors, respectively. These NPs can be loaded with the anticancer drug doxorubicin (DOX): BMC-DOX has high tumor inhibition effects both in vitro and in vivo due to combined Mn2+-mediated chemodynamic therapy and DOX-induced chemotherapy. This tumor-specific actuating nanocarrier might be a promising candidate for clinical translation.

Carbamoylmannose enhances the tumor targeting ability of supramolecular nanoparticles formed through host-guest complexation of a pair of homopolymers.

Conjugation of sugars to antitumor drugs can facilitate drug binding to tumor cells and the saccharide motifs of bleomycins (BLMs) play a crucial role in tumor-seeking. Here, we synthesized BLM monosaccharide, carbamoylmannose, and subsequently prepared carbamoylmannose decorated platinum-incorporating supramolecular nanoparticles formed through the host-guest complexation of poly(N-vinylpyrrolidone) and poly(aspartic acid). The targeting effects of carbamoylmannose decorated supramolecular nanoparticles in various cancer cells and tumor-bearing mice were investigated. It was found that the nanoparticles showed a specific in vitro and in vivo carbamoylmannose-mediated cellular uptake and drug delivery. The cellular uptake of the nanoparticles followed the receptor-mediated endocytosis mechanism in cancer cells but not in healthy cells. In a murine hepatic H22 tumor model, it was demonstrated that the carbamoylmannose moiety increased the plasma concentration, tumor targeting ability and tumor penetration of the nanoparticles, leading to high tumor accumulation and superior antitumor efficacy. This carbamoylmannose molecule may bring an opportunity to design and construct inexpensive but highly efficient drug and gene delivery systems in the future.

Smart conjugated polymer nanocarrier for healthy weight loss by negative feedback regulation of lipase activity.

Healthy weight loss represents a real challenge when obesity is increasing in prevalence. Herein, we report a conjugated polymer nanocarrier for smart deactivation of lipase and thus balancing calorie intake. After oral administration, the nanocarrier is sensitive to lipase in the digestive tract and releases orlistat, which deactivates the enzyme and inhibits fat digestion. It also creates negative feedback to control the release of itself. The nanocarrier smartly regulates activity of the lipase cyclically varied between high and low levels. In spite of high fat diet intervention, obese mice receiving a single dose of the nanocarrier lose weight over eight days, whereas a control group continues the tendency to gain weight. Daily intragastric administration of the nanocarrier leads to lower weight of livers or fat pads, smaller adipocyte size, and lower total cholesterol level than that of the control group. Near-infrared fluorescence of the nanocarrier reveals its biodistribution.

Platinum-Incorporating Poly(N-vinylpyrrolidone)-poly(aspartic acid) Pseudoblock Copolymer Nanoparticles for Drug Delivery.

Cisplatin-incorporating pseudoblock copolymer nanoparticles with high drug loading efficiency (ca. 50%) were prepared built on host-guest inclusion complexation between ß-cyclodextrin end-capped poly(N-vinylpyrrolidone) block and admantyl end-capped poly(aspartic acid) block, followed by the coordination between cisplatin and carboxyl groups in poly(aspartic acid). The host-guest interaction between the two polymer blocks was examined by two-dimensional nuclear overhauser effect spectroscopy. The size and morphology of nanoparticles formed were characterized by dynamic light scattering, zeta potential, transmission electron microscopy, and atomic force microscopy. The size control of nanoparticles was carried out by varying the ratio of poly(N-vinylpyrrolidone) to poly(aspartic acid). The nanoparticles were stable in the aqueous medium with different pH values but disintegrated in the medium containing Cl(-) ions. The in vitro and in vivo antitumor effects of cisplatin-loaded nanoparticles were evaluated. The biodistribution of the nanoparticles in vivo was studied by noninvasive near-infrared fluorescence imaging and ion-coupled plasma mass spectrometry. It was found that cisplatin-loaded nanoparticles could effectively accumulate in the tumor site and exhibited significant superior in vivo antitumor activity to the commercially available free cisplatin by combining the tumor volume, body weight, and survival rate measurements.

Hyaluronic acid nanogels with enzyme-sensitive cross-linking group for drug delivery.

A methacrylation strategy was employed to functionalize hyaluronic acid and prepare hyaluronic acid (HA) nanogels. Dynamic light scattering, zeta potential analyzer and electron microscopy were utilized to characterize the nanogels and their enzyme-degradability in vitro. It was found that these nanogels had a spherical morphology with the diameter of about 70nm, and negative surface potential. When doxorubicin (DOX) was loaded into the nanogels, the diameter decreased to approximately 50nm with a drug loading content of 16% and encapsulation efficiency of 62%. Cellular uptake examinations showed that HA nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs) which both overexpress CD44 receptor. Near-infrared fluorescence imaging, biodistribution and penetration examinations in tumor tissue indicated that the HA nanogels could efficiently accumulate and penetrate the tumor matrix. In vivo antitumor evaluation found that DOX-loaded HA nanogels exhibited a significantly superior antitumor effect.

pH-Responsive and near-infrared-emissive polymer nanoparticles for simultaneous delivery, release, and fluorescence tracking of doxorubicin in vivo.

Dextran modified with pendant acetals is used to load doxorubicin (DOX) and a near-infrared-emissive conjugated polymer (BTTPF), and this aims to provide selective drug release at therapeutic targets including tumors. The BTTPF is applicable to tracking the anticancer drug release through the change of Förster resonance energy transfer efficiency between doxorubicin and BTTPF during degradation of the nanoparticles in vivo.